Growth hormone deficiency after traumatic brain injury: Current insights and the need for preclinical modeling

Approximately 50 million people worldwide live with disabilities caused by traumatic brain injury (TBI), highlighting its profound global impact on long-term health and quality of life. A growing body of evidence indicates that hypothalamic-pituitary (HP) axis dysregulation is a critical contributor to chronic TBI morbidity, with growth hormone deficiency (GHD) emerging as the most common diagnosis. Clinicians may misattribute the delayed and nonspecific symptoms of GHD to the broader constellation of TBI-related symptoms or prioritize more immediate medical concerns, which can delay diagnosis and treatment. Emerging clinical and preclinical studies support both the occurrence of abnormal GH secretion following TBI and the potential efficacy of GH replacement in reversing many GHD-related impairments; however, several critical knowledge gaps remain. These include unclear or variable pathophysiological mechanisms underlying GHD development, limitations in diagnostic testing protocols, lack of consensus on dosing adjustments as a function of age and sex, and inconsistent clinical responses to GH therapy likely due to incomplete understanding of the underlying processes, timing, patient selection, and outcome measures. Additionally, opportunities to evaluate novel GH-related interventions and their long-term outcomes remain limited. This review summarizes these challenges, synthesizes the current preclinical literature, and proposes strategies to address these gaps through the development of more robust and translatable animal models that can systematically test these variables and ultimately improve outcomes for patients with TBI-induced GHD.